This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The need for new therapeutic drugs to combat bacterial infections is significant and increasing. Despite intensive effort over many decades and dramatic advances in target identification, combinatorial chemistry, and in small molecule screening, few new antibiotics have been introduced, and most of these do not act on new targets. MurB is an unexploited target in bacterial cell wall biosynthesis. The specific goal of this proposal is to discover MurB-specific antimicrobials using structure-based drug design (SBDD). At Trius, we have successfully crystallized a gram-negative MurB ortholog complexed with several of our proprietary inhibitors, and determined the structures to high resolution. Using SBDD, we have generated potent MurB inhibitors with multiple chemical scaffolds. 3-D structural information on MurB complexes with these new inhibitors will provide essential information that will allow us to transform our inhibitor leads into clinical candidates.